Zirconium-89 (89Zr) is a positron-emitting radionuclide that is used in medical imaging applications. In particular, it is used in positron emission tomography (PET) for cancer detection and imaging. It has a longer half-life (t1/2=79.3 hours) than other radionuclides used for medical imaging, such as 18F. For example, 18F has a t1/2 of 110 minutes, which means that its use requires close proximity to a cyclotron facility and rapid and high-yielding synthesis techniques for the preparation of the agents into which it is incorporated. 89Zr is not plagued by these same problems, which makes 89Zr particularly attractive for use in medical imaging applications.
Desferrioxamine (DFO) is a bacterial siderophore that has been used since the late 1960s to treat iron overload. The three hydroxamic acid groups in DFO form co-ordination bonds with Fe3+ ions, essentially making DFO a hexadentate ligand that chelates the Fe3+ ions. Due to the co-ordination geometry of 89Zr, DFO has also been used as a chelator for 89Zr in PET imaging applications (Holland, J. P. et al (2012) Nature 10:1586).
Other DFO-based radioisotope chelators have also been prepared for use in PET imaging applications. These include N-succinyl-desferrioxamine-tetrafluorophenol ester (N-suc-DFO-TFP ester) p-isothiocyanatobenzyl-desferrioxamine (DFO-Bz-NCS, also known as DFO-Ph-NCS) and desferrioxamine-maleimide (DFO-maleimide). All of these chelators can be conjugated with antibodies or antibody fragments to provide a means of targeting the imaging agent to the tumour to be imaged.
However, these chelators suffer from a number of disadvantages. The synthesis of N-suc-DFO-TFP ester involves the addition of Fe3+, to prevent the reaction of the tetrafluorophenol ester with one of the hydroxamate groups of desferrioxamine (DFO). Upon completion of the synthesis (which includes the step of coupling N-suc-DFO-TFP ester to an antibody), the Fe3+ then needs to be removed. This is achieved using a 100-fold molar excess of EDTA at a pH of 4.2-4.5. These conditions can be detrimental to pH-sensitive antibodies.
With regard to DFO-Bz-NCS, if this compound is added to an antibody solution too quickly without shaking or proper mixing, DFO-Bz-NCS causes the formation of antibody aggregates. In addition, the stability of the radiolabelled and antibody-conjugated chelators is a concern when stored for extended periods of time, and buffers containing chloride ions need to be avoided as they result in detachment of the radionuclide from the complex.
DFO-maleimide conjugates to antibodies via Michael addition to thiol groups. There are two main issues with this. The first is that Michael additions to thiols can lead to mixtures of isomers. This is a disadvantage because the isomers may interact in different ways with biological systems. The second issue is that Michael addition to thiol groups is reversible. This increases the risk that the DFO-maleimide-radionulide complex will dissociate from the antibody, resulting in distribution of the complex throughout the body. This not only decreases the imaging selectivity but also increases the likelihood of toxic side effects as the radiation emitted from the radionuclide in the complex interacts with other organs.
Therefore, there is a need to develop new agents for use with radioisotopes, which do not have these drawbacks.
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